US4844900A - Therapeutic agents in the form of submicroscopic particles against Leishmaniasis and pharmaceutical compositions containing them - Google Patents
Therapeutic agents in the form of submicroscopic particles against Leishmaniasis and pharmaceutical compositions containing them Download PDFInfo
- Publication number
- US4844900A US4844900A US07/105,257 US10525787A US4844900A US 4844900 A US4844900 A US 4844900A US 10525787 A US10525787 A US 10525787A US 4844900 A US4844900 A US 4844900A
- Authority
- US
- United States
- Prior art keywords
- particles
- submicroscopic
- cyanoacrylate
- leishmaniasis
- polymerization
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/51—Nanocapsules; Nanoparticles
- A61K9/5107—Excipients; Inactive ingredients
- A61K9/513—Organic macromolecular compounds; Dendrimers
- A61K9/5138—Organic macromolecular compounds; Dendrimers obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P33/00—Antiparasitic agents
- A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Definitions
- the present invention relates to new therapeutic agents against Leishmaniasis, and to pharmaceutical compositions containing them.
- Leishmaniasis denotes a group of conditions which are caused in man and other mammals by different species of parasites of the genu Leishmania. The most important species are Leishmania tropica, Leishmania aethiopica, Leishmania mexicana, Leishmania braziliensis and Leishmania donovani [F. Wunderlich and E. Schurr, Biologie in sti Zeit 14 (1984), 111-120].
- the object of the invention is consequently to obtain new therapeutic agents against Leishmaniasis which are less toxic at equal activity than the traditional active principles, or which have higher activity for approximately equal toxicity.
- these submicroscopic polymeric particles which contain a biologically active substance may be used for the treatment of many diseases, and in particular certain types of cancer.
- These particles containing a biologically active substance may be administered parenterally and afford, in particular, the advantage of being biodegradable and of exerting a prolonged therapeutic action which is more effective than that which can be obtained by the administration of the biologically active substance alone (not contained in particles).
- the toxicity of the particles containing the substance is lower than that of the biologically active substance alone.
- the submicroscopic particles prepared by the polymerization of cyanoacrylic acid derivatives are active against the known forms of Leishmaniasis, this being the case even when these particles do not contain any pharmaceutical agent known for its activity against Leishmaniasis. It has been found that, when administered parenterally, these particles, free from other substances, exert a very marked therapeutic effect against Leishmaniasis resembling that of the drugs known to be active against this disease, while not having the toxicity of these drugs.
- the toxicity and the adverse side effects of the chemotherapeutic agents are markedly reduced when the latter are in adsorbed or absorbed form in the submicroscopic particles.
- the subject of the invention is hence a therapeutic agent against Leishmaniasis which consists of submicroscopic particles whose diameter is less than 500 nanometers, the particles being obtained by the micellar polymerization of at least one alkyl cyanoacrylate.
- submicroscopic particles based on polymeric alkyl cyanoacrylate in which the linear or branched alkyl chain comprises 1 to 12 carbon atoms, and especially 4 to 7 carbon atoms, are employed.
- the submicroscopic particles are obtained by the copolymerization of at least two different alkyl cyanoacrylates.
- these particles may be obtained by the micellar polymerization of isobutyl cyanoacrylate (2-methylpropyl cyanoacrylate) and/or isohexyl cyanoacrylate (2-ethylbutyl cyanoacrylate).
- the submicroscopic particles which constitute the therapeutic agents according to the invention may be prepared according to the processes described in the documents EP-B-0,007,895 or EP-B-0,064,967, and consist of the abovementioned polymers formed by polymerization or copolymerization.
- This therapeutic action can, if desired, be made still more effective is use is made of polymeric submicroscopic particles containing at least one substance known to be active against Leishmaniasis.
- compositions to be administered parenterally and containing at least one therapeutic agent according to the invention in combination with a suitable vehicle.
- the subject of the invention is also such pharmaceutical compositions containing, in addition, amphotericine B.
- the activity of therapeutic agents according to the invention was tested on white rate (average weight: 340 g) which were inoculated with a single dose of 50 ⁇ 10 6 causal agents of the condition (Leishmania donovani).
- test animals were treated by means of various therapeutic agents 30 days after the inoculation.
- Each treatment consisted of three intracardiac injections, each of 1 ml, administered at 7-day intervals, except in the case of dehydroemetine alone which, on account of its high cardiac toxicity, was injected intraperitoneally.
- the therapeutic agents were injected intravenously; the treatment began 30 days after the inoculation and consisted of 3 injections of 0.5 ml, administered at 7-day intervals.
- the causal agents present per 100 normal nucleated spleen cells were determined and compared with those found in untreated controls.
- the therapeutic agents were injected intraveneously; the treatment was begun 30 days after the inoculation and consisted of 3 injections of 1 ml, administered at 7-day intervals.
Abstract
The invention relates to new therapeutic agents against Leishmaniasis.
These therapeutic agents consist of submicroscopic particles whose diameter is less than 500 nanometers, the particles being obtained by the micellar polymerization of an alkyl cyanoacrylate in which the alkyl chain contains from 1 to 12 carbon atoms.
The therapeutic agents according to the invention may be administered parenterally.
Description
1. Field of the Invention
The present invention relates to new therapeutic agents against Leishmaniasis, and to pharmaceutical compositions containing them.
The term Leishmaniasis denotes a group of conditions which are caused in man and other mammals by different species of parasites of the genu Leishmania. The most important species are Leishmania tropica, Leishmania aethiopica, Leishmania mexicana, Leishmania braziliensis and Leishmania donovani [F. Wunderlich and E. Schurr, Biologie in unserer Zeit 14 (1984), 111-120].
The known pharmaceutical agents which are universally administered against this condition, namely, in particular, dehydroemetine and amphotericin B, exert, apart from the desired activity, very toxic and adverse side effects.
The object of the invention is consequently to obtain new therapeutic agents against Leishmaniasis which are less toxic at equal activity than the traditional active principles, or which have higher activity for approximately equal toxicity.
2. Description of the prior art
From the documents EP-B-0,007,895 and EP-B-0,064,967, submicroscopic particles that are obtained by the micellar polymerization of alkyl cyanoacrylates, and which contain a biologically active substance in absorbed or adsorbed form, are known.
As stated in these documents, these submicroscopic polymeric particles which contain a biologically active substance may be used for the treatment of many diseases, and in particular certain types of cancer. These particles containing a biologically active substance may be administered parenterally and afford, in particular, the advantage of being biodegradable and of exerting a prolonged therapeutic action which is more effective than that which can be obtained by the administration of the biologically active substance alone (not contained in particles). In addition, the toxicity of the particles containing the substance is lower than that of the biologically active substance alone.
It has been discovered, surprisingly, that the submicroscopic particles prepared by the polymerization of cyanoacrylic acid derivatives, according to the processes described in the documents EP-B-0,007,895 and EP-B-0,064,967, are active against the known forms of Leishmaniasis, this being the case even when these particles do not contain any pharmaceutical agent known for its activity against Leishmaniasis. It has been found that, when administered parenterally, these particles, free from other substances, exert a very marked therapeutic effect against Leishmaniasis resembling that of the drugs known to be active against this disease, while not having the toxicity of these drugs.
Since it is known, following many investigations, that these submicroscopic particles based on polymers of alkyl cyanoacrylates are only slightly toxic, or are nontoxic, at least as regards the quantities administered for therapeutic purposes, these pure submicroscopic particles free from other active principles are suitable as effective therapeutic agents against Leishmaniasis.
It has been found, in addition, that the simultaneous administration of certain chemotherapeutic agents, known for their activity against Leishmaniasis, and submicroscopic particles based on polymers of alkyl cyanoacrylate enables a therapeutic effect to be attained which is superior to that which is obtained with the said submicroscopic particles alone or with the said chemotherapeutic agents alone.
When the said chemotherapeutic agents are used simultaneously with the said submicroscopic particles, the toxicity and the adverse side effects of the chemotherapeutic agents are markedly reduced when the latter are in adsorbed or absorbed form in the submicroscopic particles.
The subject of the invention is hence a therapeutic agent against Leishmaniasis which consists of submicroscopic particles whose diameter is less than 500 nanometers, the particles being obtained by the micellar polymerization of at least one alkyl cyanoacrylate.
More specifically, submicroscopic particles based on polymeric alkyl cyanoacrylate in which the linear or branched alkyl chain comprises 1 to 12 carbon atoms, and especially 4 to 7 carbon atoms, are employed.
According to one embodiment, the submicroscopic particles are obtained by the copolymerization of at least two different alkyl cyanoacrylates.
In particular, these particles may be obtained by the micellar polymerization of isobutyl cyanoacrylate (2-methylpropyl cyanoacrylate) and/or isohexyl cyanoacrylate (2-ethylbutyl cyanoacrylate).
The submicroscopic particles which constitute the therapeutic agents according to the invention may be prepared according to the processes described in the documents EP-B-0,007,895 or EP-B-0,064,967, and consist of the abovementioned polymers formed by polymerization or copolymerization.
It is surprising that these pure polymeric submicroscopic particles, free from other active principles, exert a very effective therapeutic action against Leishmaniasis, this action resembling that of the drugs known to be active against this disease.
This therapeutic action can, if desired, be made still more effective is use is made of polymeric submicroscopic particles containing at least one substance known to be active against Leishmaniasis.
In particular, use may thus be made of particles charged with dehydroemetine and/or amphotericine B.
The therapeutic agents according to the invention contain the submicroscopic particles, containing or not containing another antiparasitic substance, in the form of a suspension or colloidal solution in physiologically compatible solutions, or alternatively are dry powders which are brought into suspension or colloidal solution before administration in physiological compatible solutions, for example sodium chloride or dextrose solution.
The subject of the invention is also pharmaceutical compositions to be administered parenterally and containing at least one therapeutic agent according to the invention in combination with a suitable vehicle.
The subject of the invention is also such pharmaceutical compositions containing, in addition, amphotericine B.
The activity of therapeutic agents according to the invention was tested on white rate (average weight: 340 g) which were inoculated with a single dose of 50×106 causal agents of the condition (Leishmania donovani).
The test animals were treated by means of various therapeutic agents 30 days after the inoculation.
Each treatment consisted of three intracardiac injections, each of 1 ml, administered at 7-day intervals, except in the case of dehydroemetine alone which, on account of its high cardiac toxicity, was injected intraperitoneally.
The experimental doses injected (each having a suitable content of active principle):
(a) dehydroemetine in aqueous solution at a concentration of 1.2 mg per ml,
(b) submicroscopic particles based on polymerized isohexyl cyanoacrylate not containing any other active substance, in aqueous suspension at a concentration of 24 mg per ml,
(c) submicroscopic particles based on polymerized hexyl cyanoacrylate containing 5% of dehydroemetine (each ml of the suspension contains 24 mg of submicroscopic particles and 1.2 mg of dehydroemetine).
After the treatment, the causal agents present in the spleen were determined and compared with those found in similarly inoculated but untreated animals
______________________________________
Results
Causal agents of the
Reduction in
condition, per gram
the causal
Treatment of spleen agents (%)
______________________________________
-- 36.015 × 10.sup.6
a 4.870 × 10.sup.6
86.5
b 6.550 × 10.sup.6
81.8
c 0.585 × 10.sup.6
98.4
______________________________________
Other rats, of average weight 300 g, received a single dose of 12×106 causal agents of the condition.
The therapeutic agents were injected intravenously; the treatment began 30 days after the inoculation and consisted of 3 injections of 0.5 ml, administered at 7-day intervals.
Experimental doses injected:
(a') dehydroemetine in aqueous solution, in the proportion of 1.75 mg per kg of rat,
(b') submicroscopic particles based on polymerized isohexyl cyanoacrylate, in aqueous suspension, in the proportion of 35 mg per kg of rat,
(c') submicroscopic particles based on polymerized isohexyl cyanoacrylate containing dehydroemetine (in the proportion of 1.75 mg of dehydroemetine and 35 mg of submicroscopic particles per kg of rat).
After treatment, the causal agents present per 100 normal nucleated spleen cells were determined and compared with those found in untreated controls.
______________________________________
Results
Causal agents of the
Reduction in
condition, per 100
the causal
Treatment spleen cells agents (%)
______________________________________
-- 28
a' 16 42.86
b' 12 57.1
c' 12 57.1
______________________________________
The activity of therapeutic agents according to the invention was tested in a similar manner to that of Example 2, but amphotericin B was used instead of dehydroemetine as the biologically active substance.
Rats of average weight 300 g received a single dose of 12×106 causal agents of the condition.
The therapeutic agents were injected intraveneously; the treatment was begun 30 days after the inoculation and consisted of 3 injections of 1 ml, administered at 7-day intervals.
Experimental doses administered:
(a") amphotericin B in aqueous solution, in the proportion of 2.5 mg per kg of rat,
(b") submicroscopic particles based on polymerized isohexyl cyanoacrylate, in aqueous suspension, in the proportion of 35 mg per kg of rat,
(c") submicroscopic particles based on polymerized isohexyl cyanoacrylate containing amphotericin B (in the proportion of 2.5 mg of amphotericin B and 35 mg of submicroscopic particles per kg of rat).
After treatment, the causal agents present per gram of spleen were determined and compared with those found in controls.
______________________________________
Results
Causal agents of the
Reduction in
condition, per gram
the causal
Treatment spleen cells agents (%)
______________________________________
-- 11 × 10.sup.6
a" 2.8 × 10.sup.6
74.5
b" 4.8 × 10.sup.6
56.5
c" 2 × 10.sup.6
81.8
______________________________________
Claims (11)
1. A therapeutic composition for the treatment of Leishmaniasis that is relatively nontoxic in therapeutic quantities, consisting essentially of submicroscopic particles whose diameter is less than 500 nanometers as the sole essential therapeutic agent, the particles being obtained by micellar polymerization of at least one alkyl cyanoacrylate in which the linear or branched alkyl chain contains from 1 to 12 carbon atoms and wherein the particles are combined only with a nontoxic pharmaceutically acceptable vehicle, wherein the particles are the sole treating agent and these are free of substances known to be active against Leishmaniasis.
2. A therapeutic composition for the treatment of Leishmaniasis that is relatively nontoxic in therapeutic quantities, comprising submicroscopic particles whose diameter is less than 500 nanometers as the sole essential therapeutic agent, the particles being obtained by polymerization of at least one alkyl cyanoacrylate in which the linear or branched alkyl chain contains from 5 to 12 carbon atoms wherein the particles are the sole treating agent and these are free of substances known to be active against Leishmaniasis.
3. The therapeutic composition as claimed in claim 2, further comprising submicroscopic particles obtained by the copolymerization of at least two different alkyl cyanoacrylates in which the linear or branched alkyl chain contains from 1 to 12 carbon atoms.
4. The therapeutic composition as claimed in claim 2, wherein the submicroscopic particles are obtained by the polymerization of 2-methylpropyl cyanoacrylate.
5. The therapeutic composition as claimed in claim 2, wherein the submicroscopic particles are obtained by the polymerization of 2-ethylbutyl cyanoacrylate.
6. A pharmaceutical composition that is relatively nontoxic in therapeutic quantities in a form suitable to be administered parentally for the treatment of Leishmaniasis, comprising at least one therapeutic agent consisting essentially of submicroscopic particles whose diameter is less than 500 nanometers, the particles being obtained by micellar polymerization of at least one alkyl cyanoacrylate in which the linear or branched alkyl chain contains from 1 to 12 carbon atoms, in combination with and combined only with a suitable nontoxic vehicle, wherein the particles are the sole treating agent and these are free of substances known to be active against Leishmaniasis.
7. The pharmaceutical composition as claimed in claim 6, in which the submicroscopic particles are obtained by polymerization of at least one alkyl cyanoacrylate in which the linear or branched alkyl chain contains from 5 to 12 carbon atoms.
8. The pharmaceutical composition as claimed in claim 7, in which the submicroscopic particles are obtained by the polymerization of 2-methylpropyl cyanoacrylate.
9. The pharmaceutical composition as claimed in claim 7, in which the submicroscopic particles are obtained by the polymerization of 2-ethylbutyl cyanoacrylate.
10. A method for treating Leishmaniasis, which comprises administering to a host in need of such treatment, an effective amount of submicroscopic particles having a diameter of less than 500 nanometers, the particles being obtained by micellar polymerization of at least one alkyl cyanoacrylate in which the linear or branched chain contains from 1 to 12 carbon atoms, wherein the particles are the sole treating agent and these are free of substances known to be active against Leishmaniasis.
11. A method for treating Leishmaniasis as claimed in claim 10, wherein the particles are parentally administered to the host.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR8613999A FR2604903B1 (en) | 1986-10-08 | 1986-10-08 | THERAPEUTIC AGENTS IN THE FORM OF SUBMICROSCOPIC PARTICLES AGAINST PARASITOSIS AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM |
| FR8613999 | 1986-10-08 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| US4844900A true US4844900A (en) | 1989-07-04 |
Family
ID=9339662
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| US07/105,257 Expired - Lifetime US4844900A (en) | 1986-10-08 | 1987-10-07 | Therapeutic agents in the form of submicroscopic particles against Leishmaniasis and pharmaceutical compositions containing them |
Country Status (7)
| Country | Link |
|---|---|
| US (1) | US4844900A (en) |
| EP (1) | EP0269598B1 (en) |
| JP (1) | JPS6396121A (en) |
| AT (1) | ATE62413T1 (en) |
| CA (1) | CA1293446C (en) |
| DE (2) | DE3769287D1 (en) |
| FR (1) | FR2604903B1 (en) |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1997049387A1 (en) * | 1996-06-27 | 1997-12-31 | G.D. Searle And Co. | Particles comprising amphiphilic copolymers, having a cross-linked shell domain and an interior core domain, useful for pharmaceutical and other applications |
| US5776904A (en) * | 1990-11-16 | 1998-07-07 | Nippon Shinyaku Co., Ltd. | Dispersion preparation |
| US6177062B1 (en) | 1988-02-05 | 2001-01-23 | Schering Aktiengesellschaft | Agents and methods for enhancing contrast in ultrasound imaging |
| WO2006015519A1 (en) * | 2004-08-11 | 2006-02-16 | Yangde Zhang | A method of preparation of cetyltriethyl ammonium bromide-midified polybutylcyanoacrylate nanoparticles |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2015129793A1 (en) * | 2014-02-27 | 2015-09-03 | 昇一 城武 | Antiviral drug |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4186183A (en) * | 1978-03-29 | 1980-01-29 | The United States Of America As Represented By The Secretary Of The Army | Liposome carriers in chemotherapy of leishmaniasis |
| EP0007895A1 (en) * | 1978-07-19 | 1980-02-06 | Patrick Couvreur | Biodegradable nanoparticles, pharmaceutical compositions containing them and process for their preparation |
| EP0064967A1 (en) * | 1981-04-24 | 1982-11-17 | N.V. Sopar S.A. | Process for producing submicroscopic particles, particles obtained in that way and pharmaceutical compositions containing them |
| US4489055A (en) * | 1978-07-19 | 1984-12-18 | N.V. Sopar S.A. | Process for preparing biodegradable submicroscopic particles containing a biologically active substance and their use |
-
1986
- 1986-10-08 FR FR8613999A patent/FR2604903B1/en not_active Expired
-
1987
- 1987-10-07 CA CA000548791A patent/CA1293446C/en not_active Expired - Fee Related
- 1987-10-07 JP JP62253439A patent/JPS6396121A/en active Pending
- 1987-10-07 US US07/105,257 patent/US4844900A/en not_active Expired - Lifetime
- 1987-10-08 EP EP87870141A patent/EP0269598B1/en not_active Expired - Lifetime
- 1987-10-08 DE DE8787870141T patent/DE3769287D1/en not_active Expired - Fee Related
- 1987-10-08 DE DE198787870141T patent/DE269598T1/en active Pending
- 1987-10-08 AT AT87870141T patent/ATE62413T1/en not_active IP Right Cessation
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4186183A (en) * | 1978-03-29 | 1980-01-29 | The United States Of America As Represented By The Secretary Of The Army | Liposome carriers in chemotherapy of leishmaniasis |
| EP0007895A1 (en) * | 1978-07-19 | 1980-02-06 | Patrick Couvreur | Biodegradable nanoparticles, pharmaceutical compositions containing them and process for their preparation |
| US4489055A (en) * | 1978-07-19 | 1984-12-18 | N.V. Sopar S.A. | Process for preparing biodegradable submicroscopic particles containing a biologically active substance and their use |
| EP0064967A1 (en) * | 1981-04-24 | 1982-11-17 | N.V. Sopar S.A. | Process for producing submicroscopic particles, particles obtained in that way and pharmaceutical compositions containing them |
Non-Patent Citations (6)
| Title |
|---|
| Chemical Abstracts, vol. 104, No. 20, May 19, 1986, p. 384, No. 174575x, Columbus, Ohio, US; M. S. El Samaligy et al. * |
| Chemical Abstracts, vol. 104, No. 20, May 19, 1986, p. 384, No. 174575x, Columbus, Ohio, US; M. S. El-Samaligy et al. |
| Chemical Abstracts, vol. 105, No. 21, Nov. 24, 1986, p. 404, No. 187450y, Columbus, Ohio, US; L. Golightly et al. * |
| Chemical Abstracts, vol. 72, No. 5, Feb. 2, 1970, p. 174, No. 20279n, Columbus, Ohio, US; L. M. Gordeeva et al. * |
| Chemical Abstracts, vol. 73, 1970, p. 226, No. 129274d, Columbus, Ohio, U.S.; P. J. Van Dijck et al. * |
| Chemical Abstracts, vol. 98, No. 21, May 23, 1983, p. 364, No. 185458v, Columbus, Ohio, US; J. Kreuter. * |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6177062B1 (en) | 1988-02-05 | 2001-01-23 | Schering Aktiengesellschaft | Agents and methods for enhancing contrast in ultrasound imaging |
| US5776904A (en) * | 1990-11-16 | 1998-07-07 | Nippon Shinyaku Co., Ltd. | Dispersion preparation |
| WO1997049387A1 (en) * | 1996-06-27 | 1997-12-31 | G.D. Searle And Co. | Particles comprising amphiphilic copolymers, having a cross-linked shell domain and an interior core domain, useful for pharmaceutical and other applications |
| US6383500B1 (en) | 1996-06-27 | 2002-05-07 | Washington University | Particles comprising amphiphilic copolymers, having a crosslinked shell domain and an interior core domain, useful for pharmaceutical and other applications |
| US6491903B1 (en) | 1996-06-27 | 2002-12-10 | Washington University | Particles comprising amphiphilic copolymers |
| WO2006015519A1 (en) * | 2004-08-11 | 2006-02-16 | Yangde Zhang | A method of preparation of cetyltriethyl ammonium bromide-midified polybutylcyanoacrylate nanoparticles |
Also Published As
| Publication number | Publication date |
|---|---|
| FR2604903A1 (en) | 1988-04-15 |
| CA1293446C (en) | 1991-12-24 |
| EP0269598A1 (en) | 1988-06-01 |
| FR2604903B1 (en) | 1989-01-13 |
| ATE62413T1 (en) | 1991-04-15 |
| EP0269598B1 (en) | 1991-04-10 |
| DE3769287D1 (en) | 1991-05-16 |
| DE269598T1 (en) | 1988-09-22 |
| JPS6396121A (en) | 1988-04-27 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| DE69631824T2 (en) | BIODEGRADABLE NANOPARTICLES WITH CONTROLLED RELEASE OF INSULIN | |
| EP0279379B1 (en) | Interstitial administration of perfluorchemical emulsions for reoxygenation of hypoxic tumor cells | |
| EP0263490B1 (en) | Sustained-release particulate preparation and process for preparing the same | |
| US4853218A (en) | Zinc-protamine-alpha interferon complex | |
| EP2057987B1 (en) | Pharmaceutical composition containing statin-encapsulated nanoparticle | |
| KR100735788B1 (en) | Moxifloxacin Formulation Containing Common Salt | |
| EP0706398B1 (en) | Pharmaceutical composition containing heparin, heparin fragments or their derivatives in combination with glycerol esters | |
| EP2289539B1 (en) | Zinc-free and low-zinc insulin preparations with improved stability | |
| LU84546A1 (en) | USE OF PEPTIDES AS MEDICINE | |
| CA2202397C (en) | Compositions comprising carbonate/bicarbonate buffered dichloroacetic acid and methods for treatment of metabolic and cardiovascular disorders | |
| US20070203357A1 (en) | Freeze-dried product of n-[o-(p-pivaloyloxy benzenesulfonylamino) benzoyl]glycine monosodium salt tetra-hydrate and a process for the manufacture thereof | |
| US4844900A (en) | Therapeutic agents in the form of submicroscopic particles against Leishmaniasis and pharmaceutical compositions containing them | |
| US6720011B1 (en) | Injectable composition for cancer treatment | |
| US5491150A (en) | Supplementary therpeutic agents for the treatment of immunodeficiency syndrome | |
| DE69833225T2 (en) | USE OF HISTAMINE TO INCREASE THE BLOOD CONCENTRATION OF THE HISTAMINE | |
| DE60022759T2 (en) | ERYTHROPOIETIN FORMULATIONS OF THE MULTI-DOSE TYPE | |
| JP3532580B2 (en) | Pharmaceutical composition | |
| EP0118940B1 (en) | Use of l-moprolol for the manufacture of a fluid ophthalmic composition for treating glaucoma | |
| US2920015A (en) | Long-acting vitamin b12 | |
| US5140008A (en) | Human growth hormone unit dose for the treatment of intoxicated individuals | |
| HU207455B (en) | Method for producing pharmaceutical preparations suitable for treating postischemical heart-troubles containing captoprile and in given case thrombolitic agent | |
| WO2009128357A1 (en) | Bioactive protein-containing nanoparticle composition and method for producing the same | |
| JPS633848B2 (en) | ||
| DE2759916C2 (en) | Combating malignant neoplasms | |
| WO2000021543A1 (en) | Method and composition for treating ischemia and sickle cell anemia |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| AS | Assignment |
Owner name: N.V., SOPAR S.A., RUE DUCALE, 29, 1000 BRUSSELS, B Free format text: ASSIGNMENT OF ASSIGNORS INTEREST.;ASSIGNORS:OSUNA CARILLO DE ALBORNOZ, ANTONIO;CASTANYS, SANTIAGO;REEL/FRAME:004800/0380 Effective date: 19870928 Owner name: N.V., SOPAR S.A., RUE DUCALE, 29, 1000 BRUSSELS, B Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:OSUNA CARILLO DE ALBORNOZ, ANTONIO;CASTANYS, SANTIAGO;REEL/FRAME:004800/0380 Effective date: 19870928 |
|
| STCF | Information on status: patent grant |
Free format text: PATENTED CASE |
|
| FEPP | Fee payment procedure |
Free format text: PAYOR NUMBER ASSIGNED (ORIGINAL EVENT CODE: ASPN); ENTITY STATUS OF PATENT OWNER: LARGE ENTITY |
|
| FPAY | Fee payment |
Year of fee payment: 4 |
|
| FPAY | Fee payment |
Year of fee payment: 8 |
|
| FPAY | Fee payment |
Year of fee payment: 12 |
|
| REMI | Maintenance fee reminder mailed |